Tessem Jeffery S, Jensen Jan N, Pelli Hanna, Dai Xu-Ming, Zong Xiao-Hua, Stanley E Richard, Jensen Jan, DeGregori James
Department of Biochemistry and Molecular Genetics, Program in Molecular Biology, University of Colorado Denver School of Medicine, Aurora, Colorado 80045-6511, USA.
Diabetes. 2008 Jun;57(6):1605-17. doi: 10.2337/db07-1577. Epub 2008 Mar 28.
Chronic pancreatitis, characterized by pancreatic exocrine tissue destruction with initial maintenance of islets, eventually leads to insulin-dependent diabetes in most patients. Mice deficient for the transcription factors E2F1 and E2F2 suffer from a chronic pancreatitis-like syndrome and become diabetic. Surprisingly, onset of diabetes can be prevented through bone marrow transplantation. The goal of the described studies was to determine the hematopoietic cell type responsible for maintaining islets and the associated mechanism of this protection.
Mouse models of acute and chronic pancreatitis, together with mice genetically deficient for macrophage production, were used to determine roles for macrophages in islet angiogenesis and maintenance.
We demonstrate that macrophages are essential for preventing endocrine cell loss and diabetes. Macrophages expressing matrix metalloproteinase-9 migrate to the deteriorating pancreas. E2f1/E2f2 mutant mice transplanted with wild-type, but not macrophage-deficient colony stimulating factor 1 receptor mutant (Csf1r(-/-)), bone marrow exhibit increased angiogenesis and proliferation within islets, coinciding with increased islet mass. A similar macrophage dependency for islet and islet vasculature maintenance is observed during caerulein-induced pancreatitis.
These findings demonstrate that macrophages promote islet angiogenesis and protect against islet loss during exocrine degeneration, could explain why most patients with chronic pancreatitis develop diabetes, and suggest an avenue for preventing pancreatitis-associated diabetes.
慢性胰腺炎的特征是胰腺外分泌组织遭到破坏，而胰岛最初得以保留，最终大多数患者会发展为胰岛素依赖型糖尿病。转录因子E2F1和E2F2缺陷的小鼠患有慢性胰腺炎样综合征并会发展为糖尿病。令人惊讶的是，通过骨髓移植可以预防糖尿病的发生。上述研究的目的是确定负责维持胰岛的造血细胞类型以及这种保护作用的相关机制。
利用急性和慢性胰腺炎小鼠模型以及巨噬细胞生成存在基因缺陷的小鼠，来确定巨噬细胞在胰岛血管生成和维持中的作用。
我们证明巨噬细胞对于预防内分泌细胞丢失和糖尿病至关重要。表达基质金属蛋白酶-9的巨噬细胞迁移至逐渐恶化的胰腺。移植野生型而非巨噬细胞缺陷的集落刺激因子1受体突变体（Csf1r(-/-)）骨髓的E2f1/E2f2突变小鼠，胰岛内血管生成和增殖增加，同时胰岛质量增加。在蛙皮素诱导的胰腺炎过程中，观察到胰岛和胰岛脉管系统的维持同样依赖巨噬细胞。
这些发现表明巨噬细胞可促进胰岛血管生成，并在胰腺外分泌退化过程中防止胰岛丢失，这可以解释为什么大多数慢性胰腺炎患者会发展为糖尿病，并为预防胰腺炎相关性糖尿病提供了一条途径。
